Chemoenzymatic One-Pot Cascade for the Construction of Asymmetric C-C and C-P Bonds via Formal C-H Activation

The integration of organocatalysis and enzyme catalysis in one-pot cascade processes allows for the efficient construction of complex molecular architectures with high levels of stereocontrol. However, challenges related to reaction compatibility between both processes are often a limitation for the development of efficient synthetic routes. In this study, we describe the combination of an enzymatic aerobic oxidation followed by the squaramide-mediated asymmetric formation of C-P and C-C bonds to access important building blocks such as chiral alpha-hydroxyphosphonates and beta-nitro alcohols in good yields and enantiomeric ratios. This sequential process is conducted in a one-pot fashion within a biphasic system and represents a pioneering example of a chemoenzymatic cascade involving aerobic biooxidation and an organocatalytic step operating under hydrogen-bond activation mode and under mild reaction conditions. The integration of organo- and enzyme catalysis in one-pot processes represents an efficient way to build complex molecular structures with high stereocontrol. This study demonstrates a sequential process involving enzymatic aerobic oxidation followed by squaramide-mediated asymmetric formation of C-P and C-C bonds to make important chiral synthons in good yields and enantiomeric ratios under mild reaction conditions. This process operates within a biphasic system and represents a pioneering example of a chemoenzymatic cascade combining aerobic biooxidation and organocatalytic steps operating under non-covalent activation modes. image